title: Inflammatory mechanisms in sepsis: elevated invariant natural killer T-cell numbers in mouse and their modulatory effect on macrophage function.
abstract: Invariant natural killer T cells (iNKT) cells are emerging as key mediators of innate immune cellular and inflammatory responses to sepsis and peritonitis. Invariant natural killer T cells mediate survival following murine septic shock. Macrophages are pivotal to survival following sepsis. Invariant natural killer T cells have been shown to modulate various mediators of the innate immune system, including macrophages. We demonstrate sepsis-inducing iNKT-cell exodus from the liver appearing in the peritoneal cavity, the source of the sepsis. This migration was affected by programmed death receptor 1. Programmed death receptor 1 is an inhibitory immune receptor, reported as ubiquitously expressed at low levels on iNKT cells. Programmed death receptor 1 has been associated with markers of human critical illness. Programmed death receptor 1-deficient iNKT cells failed to demonstrate similar migration. To the extent that iNKT cells affected peritoneal macrophage function, we assessed peritoneal macrophages' ability to phagocytose bacteria. Invariant natural killer T(-/-) mice displayed dysfunctional macrophage phagocytosis and altered peritoneal bacterial load. This dysfunction was reversed when peritoneal macrophages from iNKT(-/-) mice were cocultured with wild-type iNKT cells. Together, our results indicate that sepsis induces liver iNKT-cell exodus into the peritoneal cavity mediated by programmed death receptor 1, and these peritoneal iNKT cells appear critical to regulation of peritoneal macrophage phagocytic function. Invariant natural killer T cells offer therapeutic targets for modulating immune responses and detrimental effects of sepsis.
authors.affiliation: Division of Surgical Research, Department of Surgery, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, USA. dheffernan@brown.edu
authors.forename: Daithi S
authors.initials: DS
authors.lastname: Heffernan
authors.forename: Sean F
authors.initials: SF
authors.lastname: Monaghan
authors.forename: Rajan K
authors.initials: RK
authors.lastname: Thakkar
authors.forename: Mai L
authors.initials: ML
authors.lastname: Tran
authors.forename: Chun-Shiang
authors.initials: CS
authors.lastname: Chung
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gregory
authors.forename: William G
authors.initials: WG
authors.lastname: Cioffi
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala
mesh_terms: D000818:Animals; D008264:Macrophages / Q000166:cytology* / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000276:immunology; D010587:Phagocytosis / Q000502:physiology; D018805:Sepsis / Q000276:immunology*